Rapidly escalating hepcidin and associated serum iron starvation are features of the acute response to typhoid infection in humans
Background: Iron is a key pathogenic determinant of many infectious diseases. Hepcidin, the hormone responsible for governing systemic iron homeostasis, is widely hypothesized to represent a key component of nutritional immunity through regulating the accessibility of iron to invading microorganisms...
| Autori principali: | , , , , , , , , , |
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| Natura: | Journal article |
| Pubblicazione: |
Public Library of Science
2015
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| _version_ | 1826271871016894464 |
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| author | Darton, T Blohmke, C Giannoulatou, E Waddington, C Jones, C Sturges, P Webster, C Drakesmith, H Pollard, A Armitage, A |
| author_facet | Darton, T Blohmke, C Giannoulatou, E Waddington, C Jones, C Sturges, P Webster, C Drakesmith, H Pollard, A Armitage, A |
| author_sort | Darton, T |
| collection | OXFORD |
| description | Background: Iron is a key pathogenic determinant of many infectious diseases. Hepcidin, the hormone responsible for governing systemic iron homeostasis, is widely hypothesized to represent a key component of nutritional immunity through regulating the accessibility of iron to invading microorganisms during infection. However, the deployment of hepcidin in human bacterial infections remains poorly characterized. Typhoid fever is a globally significant, human-restricted bacterial infection, but understanding of its pathogenesis, especially during the critical early phases, likewise is poorly understood. Here, we investigate alterations in hepcidin and iron/inflammatory indices following experimental human typhoid challenge. Methodology/Principal Findings: Fifty study participants were challenged with Salmonella enterica serovar Typhi and monitored for evidence of typhoid fever. Serum hepcidin, ferritin, serum iron parameters, C-reactive protein (CRP), and plasma IL-6 and TNF-alpha concentrations were measured during the 14 days following challenge. We found that hepcidin concentrations were markedly higher during acute typhoid infection than at baseline. Hepcidin elevations mirrored the kinetics of fever, and were accompanied by profound hypoferremia, increased CRP and ferritin, despite only modest elevations in IL-6 and TNF-alpha in some individuals. During inflammation, the extent of hepcidin upregulation associated with the degree of hypoferremia. Conclusions/Significance: We demonstrate that strong hepcidin upregulation and hypoferremia, coincident with fever and systemic inflammation, are hallmarks of the early innate response to acute typhoid infection. We hypothesize that hepcidin-mediated iron redistribution into macrophages may contribute to S. Typhi pathogenesis by increasing iron availability for macrophage-tropic bacteria, and that targeting macrophage iron retention may represent a strategy for limiting infections with macrophage-tropic pathogens such as S. Typhi. |
| first_indexed | 2024-03-06T22:03:34Z |
| format | Journal article |
| id | oxford-uuid:4f66ba56-29ab-48d4-bf1c-69f665235386 |
| institution | University of Oxford |
| last_indexed | 2024-03-06T22:03:34Z |
| publishDate | 2015 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | oxford-uuid:4f66ba56-29ab-48d4-bf1c-69f6652353862022-03-26T16:07:01ZRapidly escalating hepcidin and associated serum iron starvation are features of the acute response to typhoid infection in humansJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:4f66ba56-29ab-48d4-bf1c-69f665235386Symplectic Elements at OxfordPublic Library of Science2015Darton, TBlohmke, CGiannoulatou, EWaddington, CJones, CSturges, PWebster, CDrakesmith, HPollard, AArmitage, ABackground: Iron is a key pathogenic determinant of many infectious diseases. Hepcidin, the hormone responsible for governing systemic iron homeostasis, is widely hypothesized to represent a key component of nutritional immunity through regulating the accessibility of iron to invading microorganisms during infection. However, the deployment of hepcidin in human bacterial infections remains poorly characterized. Typhoid fever is a globally significant, human-restricted bacterial infection, but understanding of its pathogenesis, especially during the critical early phases, likewise is poorly understood. Here, we investigate alterations in hepcidin and iron/inflammatory indices following experimental human typhoid challenge. Methodology/Principal Findings: Fifty study participants were challenged with Salmonella enterica serovar Typhi and monitored for evidence of typhoid fever. Serum hepcidin, ferritin, serum iron parameters, C-reactive protein (CRP), and plasma IL-6 and TNF-alpha concentrations were measured during the 14 days following challenge. We found that hepcidin concentrations were markedly higher during acute typhoid infection than at baseline. Hepcidin elevations mirrored the kinetics of fever, and were accompanied by profound hypoferremia, increased CRP and ferritin, despite only modest elevations in IL-6 and TNF-alpha in some individuals. During inflammation, the extent of hepcidin upregulation associated with the degree of hypoferremia. Conclusions/Significance: We demonstrate that strong hepcidin upregulation and hypoferremia, coincident with fever and systemic inflammation, are hallmarks of the early innate response to acute typhoid infection. We hypothesize that hepcidin-mediated iron redistribution into macrophages may contribute to S. Typhi pathogenesis by increasing iron availability for macrophage-tropic bacteria, and that targeting macrophage iron retention may represent a strategy for limiting infections with macrophage-tropic pathogens such as S. Typhi. |
| spellingShingle | Darton, T Blohmke, C Giannoulatou, E Waddington, C Jones, C Sturges, P Webster, C Drakesmith, H Pollard, A Armitage, A Rapidly escalating hepcidin and associated serum iron starvation are features of the acute response to typhoid infection in humans |
| title | Rapidly escalating hepcidin and associated serum iron starvation are features of the acute response to typhoid infection in humans |
| title_full | Rapidly escalating hepcidin and associated serum iron starvation are features of the acute response to typhoid infection in humans |
| title_fullStr | Rapidly escalating hepcidin and associated serum iron starvation are features of the acute response to typhoid infection in humans |
| title_full_unstemmed | Rapidly escalating hepcidin and associated serum iron starvation are features of the acute response to typhoid infection in humans |
| title_short | Rapidly escalating hepcidin and associated serum iron starvation are features of the acute response to typhoid infection in humans |
| title_sort | rapidly escalating hepcidin and associated serum iron starvation are features of the acute response to typhoid infection in humans |
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